Sleep disorders, mental health, and dry eye disease in South Korea

Dry eye disease (DED) is a multifactorial disease of the ocular surface causing severe discomfort, mild ocular irritation, fatigue, pain, visual disturbance, and foreign body sensation. Stress, depression, and sleep disorders are risk factors for DED. We aimed to investigate the association between DED symptoms and composite factors related to mental health (combined sleep duration, psychological stress perception, and history of depressed mood) in Korean adults aged ≥ 20 years in a population-based study using the 2010–2012 Korea National Health and Nutrition Examination Survey data. Symptoms of DED and data on mental health were obtained using questionnaires. Multiple logistic regression analysis was conducted to examine the association between mental health and DED, and adjusted for possible covariates. Subjects with symptoms of DED were more likely to experience short sleep duration, psychological stress perception, and a history of depressed mood [odds ratio (OR) = 1.42, 95% confidence interval (CI) 1.06–1.90; OR = 1.71, 95% CI 1.37–2.14; and OR = 1.37, 95% CI 1.06–1.77, respectively] even after correcting for demographic factors, lifestyle factors, and medical factors. Additionally, participants with symptoms of DED were more likely to experience composite factors related to mental health (OR = 1.91, 95% CI 1.07–3.39). Therefore, ophthalmologists may report difficulties in both sleep and mental health in patients with DED.

Demographics, lifestyle, and medical characteristics of the participants are shown in Table 1. Regarding demographic characteristics, we found that in comparison to those without DED symptoms, there were many cases with DED symptoms among participants aged < 30 years or ≥ 50 years, women, those with less than elementary school level education, college students, white-collar workers and those with no occupation. Regarding lifestyle characteristics, there were more cases with DED symptoms among those with underweight or normal BMI, current nonsmokers, those not exercising regularly, and participants with daily sun exposure of ≤ 2 h/day. Regarding the clinical characteristics, there were more cases with DED symptoms among pregnant participants, those with thyroid disease, and those with previous ocular surgery.
The mental health-related characteristics of the subjects with and without symptoms of DED are shown in Table 2. Compared with participants without symptoms of DED, those with symptoms of DED frequently reported a sleep duration of ≤ 5 h/night or ≤ 6 h/night, as well as psychological stress perception, history of depressed mood, and composite factors related to mental health. Table 3 shows the results of multiple logistic regression analyses of the association between DED symptoms and related mental health characteristics. Subjects with symptoms of DED were more likely to experience short sleep duration, psychological stress perception, and a history of depressed mood [odds ratio (OR) = 1.42, 95% CI 1.06-1.90; OR = 1.71, 95% CI 1.37-2.14; and OR = 1.37, 95% CI 1.06-1.77, respectively]. In addition, participants with symptoms of DED were more likely to experience composite factors related to mental health (OR = 1.91, 95% CI 1.07-3.39).

Discussion
Upon exploring the correlation between symptoms of DED and mental health-related factors among Koreans aged ≥ 20 years, this study showed that subjects with symptoms of DED were more likely to experience short sleep durations (≤ 5 h/night), psychological stress perception, and a history of depressed mood. This result is consistent with previous studies. In addition, this study also showed that subjects with symptoms of DED were most likely to experience composite factors related to mental health [combined short sleep duration (≤ 5 h/night), psychological stress perception (yes), and history of depressed mood)].
DED is a common irritating eye disease that causes pain, discomfort, burning, foreign body sensations, and blurred vision. Previous studies have evaluated the association between psychological problems and eye diseases such as age-related macular degeneration (AMD), cataract, glaucoma, and DED 19 . DED is associated with mental health issues such as depression and anxiety 20 . Wan et al. 20 found that the prevalence of depression and anxiety was greater in patients with DED than in the control group. Moreover, the prevalence and severity of depression   www.nature.com/scientificreports/ were highest in patients with primary Sjögren's syndrome, which was similar to the results obtained in this study. A meta-analysis evaluating the correlation between eye disease and depression showed that the prevalence of depression among patients with DED was 29%, 25% among patients with glaucoma, 24% among patients with AMD, and 23% among patients with cataract, showing the highest prevalence among patients with DED 19 . Depression is more closely associated with dry eye symptoms than with dry eye signs 21,22 . Irritation of the ocular surface exerts a negative effect on visual performance and daily activity 23 . Kitazawa et al. 24 evaluated the association between psychiatric symptoms and objective measures (break-up time [BUT], Schirmer value, and fluorescein staining score) in 56 DED patients. To quantify psychiatric symptoms, the Montgomery-Asberg Depression Scale (MADRS) and HAM-A (Japanese version of the Hamilton Rating Scale for Anxiety) scales were used. Subjects were divided into those with normal MADRS and HAM-A scores, and those with high MADRS and HAM-A scores, to compare the differences in the subjective symptoms and the objective measures of DED. There was a significant difference in the subjective symptoms of DED, whereas no significant difference was observed in the objective measures.
Galor et al. 25 stated that patients with depression and anxiety can experience central sensitization, which may affect pain perception. In this regard, patients with depression or anxiety may react more sensitively to ocular sensation than control participants 20 and experience persistent irritation from eye dryness, potentially causing or exacerbating mood disorders 26 . Furthermore, inflammatory cytokines play an important role in the pathogenesis of depression by triggering sickness behavior 27,28 . Lymphocytes of patients with depression activate the production of IL-1b, IL-6, and TNF, and such inflammatory pathways are known to cause neuronal damage through oxidative and nitrosative stress 27,28 . Mrugacz et al. 29 explored the correlation between inflammatory cytokine levels in tears and depression among 32 (14 male, 18 female) DED patients with an average age of 44.21 years; and observed that patients with depression had significantly higher inflammatory cytokine (IL-6, IL-17, and TNF-α) levels in tears than control participants, which reflects the severity of local immunological changes.
Thus far, little is known about the pathogenesis of DED, and it is unclear whether depression exacerbates DED. Ayaki et al. 18 hypothesized that DED causes distress, which can lead to depression and sleep disorders. Furthermore, eye pain and exposure to light resulting from DED can cause sleep disturbances, which can in turn lead to sleep disorders. Yu et al. 30 evaluated the relationship between dry eye and sleep quality in multiple dimensions in a large community-based study. Sleep quality was evaluated on multiple levels, including the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI). They found that worse CPSQI scores were associated with higher Ocular Surface Disease Index (OSDI) severity and worse OSDI scores. Magno et al. 31 evaluated the relationship between dry eye and sleep quality. The results showed that patients with dry eye were one-and-a-half times more likely to be poor sleepers, with worse outcomes in all components of the PSQI. Lee et al. 16 evaluated the association between sleep duration and dry eye syndrome (DES) in Korean adults. They showed that the prevalence of DES was 1.20 and 1.29-fold higher in the short sleep duration (5 h/day) and severe sleep disruption (≤ 4 h/day) groups, respectively, than in the optimal sleep group (6-8 h/day), showing that the prevalence of DES increased with shorter sleep duration. This is thought to be due to stress from sensory discomfort or optical disturbance experienced by patients with DED, as well as sleep difficulty from inflammatory processes, including pain and brightness due to incomplete eye closure, during sleep.
Irritating ocular symptoms can exert a negative influence on visual performance 32 through tear instability from DED, which leads to blurred vision, thereby potentially hindering daily activities. Furthermore, patients with DED can experience stress from sensory discomfort or optical disturbances, and the condition itself can cause psychological distress. Patients with Sjögren's syndrome are known to experience various sleep disorders such as pain, night awakenings, long sleep latency, and obstructive sleep apnea 18 .
It remains unclear whether poor sleep causes DED or vice versa. In this study, it was found that people who had a short sleep duration, experienced psychological stress perception, and reported a history of depressed mood had more symptoms of DED than when they had each single element depression in 301 patients with DED and 202 with other ocular surface diseases (chronic conjunctivitis/allergic conjunctivitis). They showed that the mild to severe DED group had a higher proportion of patients presenting with sleep quality problems, based on a Pittsburgh Sleep Quality Index (PSQI) of ≥ 6, as well as depression symptomology, based on a Hospital Anxiety and Depression Scale (HADS) of ≥ 5, when compared with the chronic conjunctivitis or allergic conjunctivitis groups. Li et al. 33 reported that sleep deprivation in a mouse model impaired the function of the lacrimal system and caused dry eye. Lee et al. 34 also reported that sleep deprivation could trigger dry eye by inducing tear hyperosmolarity and reducing tear secretion. Conversely, it has been shown that chronic pain and discomfort caused by DED can negatively affect sleep quality and mental health 35 . Moreover, quality of sleep improved after topical treatment for newly diagnosed DED 35 . Therefore, ophthalmologists may report difficulties in sleep and mental health together when treating patients with DED.
In some patients with DED, tear production may have been compromised by the use of somnifacients containing anticholinergic agents 36 . Chronic exposure to histamines and 5-hydroxytryptamine changes function of secretory processes, and the neuronal release of 5-hydroxytryptamine could plausibly affect the acute control of lacrimal secretion 36 . Zheng et al. 19 stated that chronic pain from dry eye disease can induce depression, and that medications used to treat depression can cause or exacerbate dry eye disease. Additionally, sleep deprivation and medication history due to psychiatric disorders may partially inhibit tear secretion since lacrimal secretion is under neural regulation. Notably, Ayaki et al. 32 found that steroid or mucin secretagogue eye drops (diquafosol and rebamipide) used to relieve severe DED symptoms could cause distress.
In addition, there is a possibility that coexisting autoimmune-related comorbidities (autoimmune diseases, psychiatric disorders, and chronic pain syndromes) may affect the relationship between dry eye and sleep. Magno et al. 31 found that one in two patients with severe dry eye syndrome had chronic diseases, such as osteoarthritis and obstructive sleep apnea syndrome, that could impair sleep quality. Accordingly, the possibility of comorbidities of dry eye should be considered when consulting patients with DED. www.nature.com/scientificreports/ A major strength of this study is that it evaluated DED in people who experienced sleep problems, psychological stress, and depressive moods. In addition, this study included 16,471 South Korean adults aged ≥ 20 years. Korea is a single-race country with uniform genetic and environmental influence. Therefore, the results of this study are more consistent than other large population-based studies and should be broadly generalizable.
However, the following limitations should be considered. First, although a cross-sectional study can identify the correlation between DED and psychiatric factors, it cannot establish a causal relationship. Longitudinal studies are required to confirm the associations observed in this study. Second, the DED and mental health variables used in the present study did not undergo an objective test, and it is not known whether the participants currently have dry eye. Nevertheless, the same diagnostic criteria for DED and mental health have been applied in previously reported studies 9,12 . In addition, according to a survey conducted by the Korean Corneal Disease Study Group, Korean corneal specialists diagnosed DED using the diagnostic criteria of the International Dry Eye Workshop or Dysfunctional Tear Syndrome Study Group guidelines. There is evidence that it has been tested on an accepted standard 37 . Third, sleep duration was evaluated through surveys. Fourth, we did not examine recent data beyond 2010 to 2012. Although many dry eye studies have been reported, few studies have been conducted using population-based national data, which formed the basis of our study. Future studies with objective evaluations of sleep quality (actigraphy, melatonin measurement, and polysomnography) in patients with DED are needed to further elucidate the role of mental health-related factors in the symptoms of DED.
In conclusion, the present study provides epidemiologic evidence that DED is associated with sleep duration, stress, and depression in the Korean population. Short sleep duration (≤ 5 h/night), psychological stress perception, and history of depressed mood were significantly associated with DED, even after controlling for demographic, lifestyle, and medical factors. Subjects with symptoms of DED were most likely to experience composite factors related to mental health [combined short sleep duration (≤ 5 h/night), psychological stress perception (yes), and history of depressed mood)]. Therefore, it is likely that ophthalmologists may report difficulties in sleep and mental health when treating patients with DED. In addition, psychological support and sleep treatment should be considered together with DED treatment.

Study design and population. The Korean National Health and Nutrition Examination Survey
(KNHANES) is a nationwide population-based cross-sectional health examination and survey conducted regularly by the Korea Centers for Disease Control and Prevention, under the Ministry of Health and Welfare. The fifth KNHANES survey was conducted between 2010 and 2012. This study used a complex, stratified, multistage probability sampling model based on national census data. Survey sample weights were used in all analyses. This was calculated by considering the sampling rate, response rate, and age/gender ratio of the reference population to provide a representative estimate of the Korean civilian population. Previous studies have described the KNHANES methodology in detail [37][38][39][40] . In addition, survey datasets are freely available on the KNHANES website.
Participants in the survey underwent a health interview comprising health examinations, an ophthalmic interview and ophthalmic examinations, and a nutrition survey. A health interview and examination were performed by trained interviewers and medical staff at the mobile examination center. The ophthalmic survey was verified by the Epidemiology Survey Committee of the Korean Ophthalmological Society, and the detailed diagnostic criteria for eye conditions used in this study have been described elsewhere 12 .
This study followed the tenets of the Declaration of Helsinki for biomedical research and was approved by Participants and data selection. We included 25,534 participants who completed the KNHANES 2010-2012. We excluded participants aged < 19 years (n = 6140), or those who had no questionnaire related to DED (n = 2599). We further excluded those without mental health characteristics (n = 324). Finally, after implementing these exclusion criteria, 16,471 participants were included in the analysis (Fig. 1).
The DED questionnaire used in this study was designed by the Korean Ophthalmology Society (KOS). For quality control, ophthalmologists are trained twice a year by the Korean Disease Control and Prevention Agency (KCDC) and KOS. The KNHANES introduced dry eye questionnaires in 2010 to evaluate the prevalence of dry eyes 37 . DED was determined based on the symptoms using a questionnaire administered by an ophthalmologist. The following questions were answered "yes" or "no": "Do your eyes tend to dryness, foreign body sensation with itching and burning or sandy feeling lately?" Asking about the symptoms of DED is a reliable diagnostic method, as there are currently no definitive clinical diagnostic tests to diagnose an individual with DED.
Sleep duration was assessed using the self-administered question, "How many hours do you usually sleep a day?" The third edition of the International Classification of Sleep Disorders generally classifies long sleepers as those sleeping for ≥ 9-10 h, and short sleepers as those sleeping for ≤ 5-6 h 41,42 . Therefore, this study classified sleep time as ≤ 5, 6, 7, 8, or ≥ 9 h/day, according to the intervals used in a previous study 43 .
Psychological stress perception was evaluated from responses indicative of cognitive complaints collected with a questionnaire using a 4-point Likert scale [1 (very much), 2 (a lot), 3 (a little), and 4 (hardly any)] to the question "How much stress do you feel in your daily life?" 44 . Psychological stress perception was classified as "yes" when the level of stress perception was very much or a lot and "no" when a little or hardly any. Participants www.nature.com/scientificreports/ were asked to respond "yes" or "no" to the following history of depressed mood questions: "During the past year, has your daily life been burdened by feelings of hopelessness or dejection for more than 2 continuous weeks?" 9 . Participants were defined as having a composite factor related to mental health when they answered positively regarding sleep duration (≤ 5 h/night), psychological stress perception (yes), and history of depressed mood (yes). Questionnaires were used to collect data on age, sex, education, household income, occupation, smoking, regular exercise, daily sun exposure, pregnancy, and a history of ocular surgery. Subjects were classified into six age groups: 20-29, 30-39, 40-49, 50-59, 60-69, and ≥ 70 years. Educational attainment was classified into the following categories: less than elementary school education, middle school, high school, and more than university. Household income was then divided into quartiles. Occupation was classified as blue collar (agriculture workers, forestry workers, fishery workers, craft and related trade workers, plant and machine operators and assemblers, and simple labor), white collar (managers, professionals, clerks, and service or sales workers), and unemployed for any reason. Current smoking was classified as yes or no (current non-smokers were either never smokers or past smokers). Regular exercise was defined as walking for > 30 min at least 5 days a week. Daily sun exposure was classified into categories of < 2, 2-5, and ≥ 5 h of typical exposure per day. Pregnancy was assessed using the question "Are you currently pregnant?" History of ocular surgery was evaluated using the question, "Have you ever had ocular surgery in the past?".
Anthropometric measurements were used to collect data on body mass index (BMI), diabetes, hypertension, thyroid disease, and rheumatoid arthritis. BMI was defined as underweight (< 18.5 kg/m 2 ), normal (≤ 18.5 to < 25 kg/m 2 ), and overweight/obesity (≥ 25 kg/m 2 ) 43 . Diabetes was evaluated using the question: "Have you ever diagnosed with diabetes by a physician?" Hypertension was defined as a systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 90 mmHg, measured during the medical examination, or currently taking antihypertensive medications 43 . Thyroid disease and rheumatoid arthritis diagnoses were classified into combined yes or no categories using the question: "Have you ever been diagnosed with thyroid disease or rheumatoid arthritis by a physician?". Statistical analyses. Weighted analysis was used to reflect the true population statistics more accurately.
Data are expressed as unweighted numbers and weighted proportions (%). The chi-square test was used to compare the demographic, lifestyle, and medical characteristics of the study population between participants with and without DED symptoms. Multiple logistic regression analysis was conducted to examine the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between mental health-related characteristics (sleep duration, psychological stress perception, and history of depressed mood) and the symptoms of DED. Demographic factors (age and sex), lifestyle factors (education, occupation, BMI, smoking, regular exercise, and daily sun exposure), and medical factors (pregnancy, thyroid disease, and history of ocular surgery) were used as covariates to calculate the adjusted odds ratios (aORs). Statistical analyses were performed using SPSS 18.0 version (SPSS Inc., Chicago, IL, USA). All reported P values were two-tailed, and values < 0.050 were considered as the threshold for statistical significance.

Data availability
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